Airway Mucosal Host Defense Is Key to Genomic Regulation of Cystic Fibrosis Lung Disease Severity.

RATIONALE: The severity of cystic fibrosis (CF) lung disease varies widely, even for Phe508del homozygotes. Heritability studies show that more than 50% of the variability reflects non-cystic fibrosis transmembrane conductance regulator (CFTR) genetic variation; however, the full extent of the pertinent genetic variation is not known. OBJECTIVES: We sought to identify novel CF disease-modifying mechanisms using an integrated approach based on analyzing "in vivo" CF airway epithelial gene expression complemented with genome-wide association study (GWAS) data. METHODS: Nasal mucosal RNA from 134 patients with CF was used for RNA sequencing. We tested for associations of transcriptomic (gene expression) data with a quantitative phenotype of CF lung disease severity. Pathway analysis of CF GWAS data (n = 5,659 patients) was performed to identify novel pathways and assess the concordance of genomic and transcriptomic data. Association of gene expression with previously identified CF GWAS risk alleles was also tested. MEASUREMENTS AND MAIN RESULTS: Significant evidence of heritable gene expression was identified. Gene expression pathways relevant to airway mucosal host defense were significantly associated with CF lung disease severity, including viral infection, inflammation/inflammatory signaling, lipid metabolism, apoptosis, ion transport, Phe508del CFTR processing, and innate immune responses, including HLA (human leukocyte antigen) genes. Ion transport and CFTR processing pathways, as well as HLA genes, were identified across differential gene expression and GWAS signals. CONCLUSIONS: Transcriptomic analyses of CF airway epithelia, coupled to genomic (GWAS) analyses, highlight the role of heritable host defense variation in determining the pathophysiology of CF lung disease. The identification of these pathways provides opportunities to pursue targeted interventions to improve CF lung health.

Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR.

BACKGROUND: Cystic fibrosis is a life-limiting disease that is caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Phe508del is the most common CFTR mutation. METHODS: We conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator, in patients 12 years of age or older who had cystic fibrosis and were homozygous for the Phe508del CFTR mutation. In both studies, patients were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary end point was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24. RESULTS: A total of 1108 patients underwent randomization and received study drug. The mean baseline FEV1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both lumacaftor-ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV1 ranged from 2.6 to 4.0 percentage points (P<0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P<0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the lumacaftor-ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor-ivacaftor groups as well. The incidence of adverse events was generally similar in the lumacaftor-ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor-ivacaftor versus 1.6% among those who received placebo. CONCLUSIONS: These data show that lumacaftor in combination with ivacaftor provided a benefit for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. (Funded by Vertex Pharmaceuticals and others; TRAFFIC and TRANSPORT ClinicalTrials.gov numbers, NCT01807923 and NCT01807949.).

Home Monitoring of Patients with Cystic Fibrosis to Identify and Treat Acute Pulmonary Exacerbations. eICE Study Results.

RATIONALE: Individuals with cystic fibrosis (CF) experience frequent acute pulmonary exacerbations, which lead to decreased lung function and reduced quality of life. OBJECTIVES: The goal of this study was to determine if an intervention directed toward early detection of pulmonary exacerbations using home spirometry and symptom monitoring would result in slower decline in lung function than in control subjects. METHODS: We conducted a multicenter, randomized trial at 14 CF centers with subjects at least 14 years old. The early intervention arm subjects measured home spirometry and symptoms electronically twice per week. Sites were notified if a participant met criteria for an exacerbation and contacted participants to determine if treatment for acute exacerbation was required. Participants in the usual care arm were seen every 3 months and were asked to contact the site if they were concerned about worsening pulmonary symptoms. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the 52-week change in FEV1. Secondary outcomes included time to first exacerbation and subsequent exacerbation, quality of life, and change in weight. A total of 267 patients were randomized, and the study arms were well matched at baseline. There was no significant difference between study arms in 52-week mean change in FEV1 slope (mean slope difference, 0.00 L, 95% confidence interval, -0.07 to 0.07; P = 0.99). The early intervention arm subjects detected exacerbations more frequently than usual care arm subjects (time to first exacerbation hazard ratio, 1.45; 95% confidence interval, 1.09 to 1.93; P = 0.01). Adverse events were not significantly different between treatment arms. CONCLUSIONS: An intervention of home monitoring among patients with CF was able to detect more exacerbations than usual care, but this did not result in slower decline in lung function. Clinical trial registered with www.clinicaltrials.gov (NCT01104402).

Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy.

Gene therapy has emerged as an alternative for the treatment of diseases refractory to conventional therapeutics. Synthetic nanoparticle-based gene delivery systems offer highly tunable platforms for the delivery of therapeutic genes. However, the inability to achieve sustained, high-level transgene expression in vivo presents a significant hurdle. The respiratory system, although readily accessible, remains a challenging target, as effective gene therapy mandates colloidal stability in physiological fluids and the ability to overcome biological barriers found in the lung. We formulated highly stable DNA nanoparticles based on state-of-the-art biodegradable polymers, poly(ß-amino esters) (PBAEs), possessing a dense corona of polyethylene glycol. We found that these nanoparticles efficiently penetrated the nanoporous and highly adhesive human mucus gel layer that constitutes a primary barrier to reaching the underlying epithelium. We also discovered that these PBAE-based mucus-penetrating DNA nanoparticles (PBAE-MPPs) provided uniform and high-level transgene expression throughout the mouse lungs, superior to several gold standard gene delivery systems. PBAE-MPPs achieved robust transgene expression over at least 4 mo following a single administration, and their transfection efficiency was not attenuated by repeated administrations, underscoring their clinical relevance. Importantly, PBAE-MPPs demonstrated a favorable safety profile with no signs of toxicity following intratracheal administration.

Overcoming the cystic fibrosis sputum barrier to leading adeno-associated virus gene therapy vectors.

Gene therapy has not yet improved cystic fibrosis (CF) patient lung function in human trials, despite promising preclinical studies. In the human CF lung, inhaled gene vectors must penetrate the viscoelastic secretions coating the airways to reach target cells in the underlying epithelium. We investigated whether CF sputum acts as a barrier to leading adeno-associated virus (AAV) gene vectors, including AAV2, the only serotype tested in CF clinical trials, and AAV1, a leading candidate for future trials. Using multiple particle tracking, we found that sputum strongly impeded diffusion of AAV, regardless of serotype, by adhesive interactions and steric obstruction. Approximately 50% of AAV vectors diffused >1,000-fold more slowly in sputum than in water, with large patient-to-patient variation. We thus tested two strategies to improve AAV diffusion in sputum. We showed that an AAV2 mutant engineered to have reduced heparin binding diffused twice as fast as AAV2 on average, presumably because of reduced adhesion to sputum. We also discovered that the mucolytic N-acetylcysteine could markedly enhance AAV diffusion by altering the sputum microstructure. These studies underscore that sputum is a major barrier to CF gene delivery, and offer strategies for increasing AAV penetration through sputum to improve clinical outcomes.

Update on key emerging challenges in cystic fibrosis.

Cystic fibrosis (CF) is a multisystem disease causing severe chronic sinopulmonary disease and loss of pancreatic exocrine function, which affects approximately 70,000 individuals worldwide. New therapeutic developments over the last few decades have resulted in a significant increase in survival, with the median predicted survival now reaching the late thirties and more and more CF patients living well into adulthood. However, with this advent of new therapies and the associated increase in survival, new challenges in CF care have also emerged. Two of these challenges, i.e. chronic methicillin-resistant Staphylococcus aureus lung infection and patient adherence to very complicated and time-consuming therapeutic regimens, are reviewed in detail here. In addition, the ultimate challenge of treating the underlying cause of CF by correcting the dysfunction of the CF transmembrane conductance regulator chloride channel is reviewed, as agents to correct channel function will likely significantly alter CF clinical outcomes and treatment approaches in the next decade.

Major discrimination due to stuttering and its association with quality of life.

PURPOSE: This study aimed to identify what types of major discrimination have been experienced by adults who stutter throughout their lives, and investigate the association between the number of different types of major discrimination events experienced and quality of life. METHODS: Measures of quality of life (Kemp Quality of Life Scale) and major discrimination (adapted Major Experiences of Discrimination Scale) were completed by 303 adults who stutter. Correlational and regression analyses were conducted with these variables. RESULTS: A majority (56%) of the participants had experienced at least one episode of major discrimination due to stuttering during their lives. The major discrimination experiences most commonly reported included not being hired for a job and being discouraged by a teacher or advisor from pursuing certain careers or jobs because of stuttering. There was a significant negative relationship between quality of life and major discrimination. Increased major discrimination predicted lower quality of life even after taking into account demographic variables and severity of physical speech disruption. CONCLUSIONS: The findings of a negative association between major discrimination and quality of life add support to the notion that reducing societal stigma related to stuttering should be a priority of the field. Discriminatory practices of listeners constitute a social-environmental barrier to communicative participation and quality of life in people who stutter and should be addressed by professionals in the field of speech-language pathology and other stakeholders.

Simulated GABA synaptic input and L-type calcium channels form functional microdomains in hypothalamic gonadotropin-releasing hormone neurons.

Hypothalamic gonadotropin-releasing hormone (GnRH) neurons integrate the multiple internal and external cues that regulate sexual reproduction. In contrast to other neurons that exhibit extensive dendritic arbors, GnRH neurons usually have a single dendrite with relatively little branching. This largely precludes the integration strategy in which a single dendritic branch serves as a unit of integration. In the present study, we identify a gradient in L-type calcium channels in dendrites of mouse GnRH neurons and its interaction with GABAergic and glutamatergic inputs. Higher levels of L-type calcium channels are in somata/proximal dendrites (i.e., 0-26 µm) and distal dendrites (∼130 µm dendrite length), but intervening midlengths of dendrite (∼27-130 µm) have reduced L-type calcium channels. Using uncaging of GABA, there is a decreasing GABAergic influence along the dendrite and the impact of GABA(A) receptors is dependent on activation of L-type calcium channels. This results in amplification of proximal GABAergic signals and attenuation of distal dendritic signals. Most interestingly, the intervening dendritic regions create a filter through which only relatively high-amplitude, low-frequency GABAergic signaling to dendrites elicits action potentials. The findings of the present study suggest that GnRH dendrites adopt an integration strategy whereby segments of single nonbranching GnRH dendrites create functional microdomains and thus serve as units of integration.

Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation.

BACKGROUND: A new approach in the treatment of cystic fibrosis involves improving the function of mutant cystic fibrosis transmembrane conductance regulator (CFTR). VX-770, a CFTR potentiator, has been shown to increase the activity of wild-type and defective cell-surface CFTR in vitro. METHODS: We randomly assigned 39 adults with cystic fibrosis and at least one G551D-CFTR allele to receive oral VX-770 every 12 hours at a dose of 25, 75, or 150 mg or placebo for 14 days (in part 1 of the study) or VX-770 every 12 hours at a dose of 150 or 250 mg or placebo for 28 days (in part 2 of the study). RESULTS: At day 28, in the group of subjects who received 150 mg of VX-770, the median change in the nasal potential difference (in response to the administration of a chloride-free isoproterenol solution) from baseline was -3.5 mV (range, -8.3 to 0.5; P=0.02 for the within-subject comparison, P=0.13 vs. placebo), and the median change in the level of sweat chloride was -59.5 mmol per liter (range, -66.0 to -19.0; P=0.008 within-subject, P=0.02 vs. placebo). The median change from baseline in the percent of predicted forced expiratory volume in 1 second was 8.7% (range, 2.3 to 31.3; P=0.008 for the within-subject comparison, P=0.56 vs. placebo). None of the subjects withdrew from the study. Six severe adverse events occurred in two subjects (diffuse macular rash in one subject and five incidents of elevated blood and urine glucose levels in one subject with diabetes). All severe adverse events resolved without the discontinuation of VX-770. CONCLUSIONS: This study to evaluate the safety and adverse-event profile of VX-770 showed that VX-770 was associated with within-subject improvements in CFTR and lung function. These findings provide support for further studies of pharmacologic potentiation of CFTR as a means to treat cystic fibrosis. (Funded by Vertex Pharmaceuticals and others; ClinicalTrials.gov number, NCT00457821.).

Stuttering, Intersectionality, and Identity: A Qualitative Analysis of the Experiences of Lesbian, Gay, and Bisexual Individuals Who Stutter.

PURPOSE: Speech-language pathologists are influential in shaping identity development for individuals who stutter, particularly as it relates to communication. This study investigated the experiences of lesbian, gay, and bisexual individuals who stutter to learn more about how multiple marginalized identities affect their psychosocial experiences. METHOD: Semi-structured interviews were conducted with seven individuals who stutter with lesbian, gay, and bisexual identities. Participants ranged in age from 22 to 60 years. Data were analyzed for themes and categories by using interpretive phenomenological analysis. RESULTS: Four primary themes were identified: (a) the importance of visibility and shared social identity connections for affirmation; (b) effects of oppressive social expectations on identity; (c) intersectionality of stuttering, gay, lesbian, and bisexual identities; and (d) effects of not being affirmed for identity. DISCUSSION: Results are discussed in the context of identity affirmation and intersectionality. Through an understanding of identity formation and psychosocial experiences of lesbian, gay, and bisexual individuals who stutter, speech-language pathologists can use identity-affirmative practices to support individuals who stutter and mitigate stigmatizing experiences. Implications focus on suggestions for the provision of identity-affirming speech-language pathology practices for students who stutter.

Self-Stigma of Stuttering: Implications for Communicative Participation and Mental Health.

PURPOSE: The purpose of this study was to determine if self-stigma-related variables predicted communicative participation and mental health in adults who stutter. A progressive model of self-stigma was theorized and tested. METHOD: Adults who stutter (N = 344) completed a survey that included measures of communicative participation, global mental health, and a variety of self-stigma-related variables including perceived enacted stigma, stigma awareness, anticipated stigma, felt stigma, stereotype agreement, and stigma application, in addition to demographic and speech-related variables. Hierarchical regression was performed to test whether self-stigma-related variables progressively explained significant variance in both communicative participation and global mental health.c Results: After controlling for demographic and speech-related variables, stigma-related variables were found to be significant predictors of both communicative participation and global mental health among adults who stutter. Most self-stigma-related variables entered later in the model predicted additional unique variance in the outcome variables than the self-stigma-related variables entered in previous steps, thus supporting the trickle-down and progressive nature of the self-stigma model theorized. CONCLUSIONS: Accounting for self-stigma in the assessment and treatment of individuals who stutter may identify and ultimately reduce environmental and personal barriers to communicative functioning and well-being in people who stutter. The self-stigma terminology and model described in this study will help practitioners, researchers, and the public better understand the process of self-stigma and how it may be associated with adverse outcomes experienced by people who stutter.

Turkish adaptation of the self-stigma of stuttering scale (4S): Study of validity and reliability (4S-TR).

PURPOSE: This study aimed to adapt the Self-Stigma of Stuttering Scale (4S) into Turkish and evaluate its factor structure, reliability, and validity in Turkish culture. METHODS: The original 4S scale was translated into Turkish (4S-TR) using a forward-backward translation technique and was administered to 350 adults who stutter (AWS). To discover latent variables evaluated on the scale, two-factor analyses were performed. Internal consistency and temporal stability were calculated to ensure reliability. Test-retest reliability correlation scores were calculated with multiple applications of the scale within about two weeks. To verify construct validity, participants also completed the Turkish versions of the Self-Esteem Rating Scale-Short Form (BSDÖ-KF) and the Satisfaction with Life Scale(YDÖ). RESULTS: The explanatory factor analysis showed three factors explaining 74.76 % of the total variance. The findings were also validated by confirmatory factor analysis. High levels of internal consistency (r = .89) and test-retest reliability (r = .96) were obtained. In terms of construct validity, our findings revealed that self-stigma has a significant negative correlation with self-esteem (r = -.41) and life satisfaction (r = -.38) as was predicted. CONCLUSIONS: The findings demonstrate preliminary evidence that the 4S-TR is a viable and valid instrument for self-stigma evaluation in three domains (stigma awareness, stereotype agreement, and self-concurrence). The 4S-TR can be applied for research and clinical purposes in Turkish.

Hormone secretion in transgenic rats and electrophysiological activity in their gonadotropin releasing-hormone neurons.

Expression of GFP in GnRH neurons has allowed for studies of individual GnRH neurons. We have demonstrated previously the preservation of physiological function in male GnRH-GFP mice. In the present study, we confirm using biocytin-filled GFP-positive neurons in the hypothalamic slice preparation that GFP-expressing somata, axons, and dendrites in hypothalamic slices from GnRH-GFP rats are GnRH1 peptide positive. Second, we used repetitive sampling to study hormone secretion from GnRH-GFP transgenic rats in the homozygous, heterozygous, and wild-type state and between transgenic and Wistar males after ~4 yr of backcrossing. Parameters of hormone secretion were not different between the three genetic groups or between transgenic males and Wistar controls. Finally, we performed long-term recording in as many GFP-identified GnRH neurons as possible in hypothalamic slices to determine their patterns of discharge. In some cases, we obtained GnRH neuronal recordings from individual males in which blood samples had been collected the previous day. Activity in individual GnRH neurons was expressed as total quiescence, a continuous pattern of firing of either low or relatively high frequencies or an intermittent pattern of firing. In males with both intensive blood sampling (at 6-min intervals) and recordings from their GnRH neurons, we analyzed the activity of GnRH neurons with intermittent activity above 2 Hz using cluster analysis on both data sets. The average number of pulses was 3.9 ± 0.6/h. The average number of episodes of firing was 4.0 ± 0.6/h. Therefore, the GnRH pulse generator may be maintained in the sagittal hypothalamic slice preparation.

Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation.

BACKGROUND: VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro. METHODS: A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo. RESULTS: The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens. CONCLUSIONS: In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit. CLINICAL TRIAL NUMBER: NCT00865904.

N-acetylcysteine enhances cystic fibrosis sputum penetration and airway gene transfer by highly compacted DNA nanoparticles.

For effective airway gene therapy of cystic fibrosis (CF), inhaled gene carriers must first penetrate the hyperviscoelastic sputum covering the epithelium. Whether clinically studied gene carriers can penetrate CF sputum remains unknown. Here, we measured the diffusion of a clinically tested nonviral gene carrier, composed of poly-l-lysine conjugated with a 10 kDa polyethylene glycol segment (CK(30)PEG(10k)). We found that CK(30)PEG(10k)/DNA nanoparticles were trapped in CF sputum. To improve gene carrier diffusion across sputum, we tested adjuvant regimens consisting of N-acetylcysteine (NAC), recombinant human DNase (rhDNase) or NAC together with rhDNase. While rhDNase alone did not enhance gene carrier diffusion, NAC and NAC + rhDNase increased average effective diffusivities by 6-fold and 13-fold, respectively, leading to markedly greater fractions of gene carriers that may penetrate sputum layers. We further tested the adjuvant effects of NAC in the airways of mice with Pseudomonas aeruginosa lipopolysaccharide (LPS)-induced mucus hypersecretion. Intranasal dosing of NAC prior to CK(30)PEG(10k)/DNA nanoparticles enhanced gene expression by up to ~12-fold compared to saline control, reaching levels observed in the lungs of mice without LPS challenge. Our findings suggest that a promising synthetic nanoparticle gene carrier may transfer genes substantially more effectively to lungs of CF patients if administered following adjuvant mucolytic therapy with NAC or NAC + rhDNase.

Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier.

Protective mucus coatings typically trap and rapidly remove foreign particles from the eyes, gastrointestinal tract, airways, nasopharynx, and female reproductive tract, thereby strongly limiting opportunities for controlled drug delivery at mucosal surfaces. No synthetic drug delivery system composed of biodegradable polymers has been shown to penetrate highly viscoelastic human mucus, such as non-ovulatory cervicovaginal mucus, at a significant rate. We prepared nanoparticles composed of a biodegradable diblock copolymer of poly(sebacic acid) and poly(ethylene glycol) (PSA-PEG), both of which are routinely used in humans. In fresh undiluted human cervicovaginal mucus (CVM), which has a bulk viscosity approximately 1,800-fold higher than water at low shear, PSA-PEG nanoparticles diffused at an average speed only 12-fold lower than the same particles in pure water. In contrast, similarly sized biodegradable nanoparticles composed of PSA or poly(lactic-co-glycolic acid) (PLGA) diffused at least 3,300-fold slower in CVM than in water. PSA-PEG particles also rapidly penetrated sputum expectorated from the lungs of patients with cystic fibrosis, a disease characterized by hyperviscoelastic mucus secretions. Rapid nanoparticle transport in mucus is made possible by the efficient partitioning of PEG to the particle surface during formulation. Biodegradable polymeric nanoparticles capable of overcoming human mucus barriers and providing sustained drug release open significant opportunities for improved drug and gene delivery at mucosal surfaces.

Uncertainty and Perceived Control as Predictors of Communicative Participation and Mental Health in Adults Who Stutter.

PURPOSE: This study examined the role of uncertainty and perceived control in predicting the communicative participation and mental health of adults who stutter. METHOD: Two hundred sixty-nine adults who stutter completed measures of uncertainty about stuttering, perceived control of stuttering, communicative participation, and global mental health. In addition, participants self-reported on a variety of demographic and speech-related measures. Correlational analyses and hierarchical regression were performed to determine associations between variables of interest. RESULTS: Uncertainty accounted for significant variance in communicative participation and global mental health after statistically controlling for the effects of demographic and speech-related variables. Perceived control accounted for significant variance in communicative participation over and above what was accounted for by demographic variables, speech-related variables, and uncertainty. CONCLUSIONS: The findings suggest that uncertainty about stuttering and perceived control of stuttering should be accounted for during assessment and intervention with adults who stutter. Interventions that specifically target uncertainty and perceived control may be useful in improving therapeutic outcomes for individuals who stutter.

Self-reported experience of bullying of students who stutter: relations with life satisfaction, life orientation, and self-esteem.

Self-reported self-esteem, life orientation, satisfaction with life, and bullying were examined in relation to victimization experiences among 54 students who stuttered and 54 students who did not stutter. Those who stuttered reported greater, i.e., clinically significant, victimization (44.4%) than students who did not stutter (9.2%). Significant differences were found between means for self-esteem and life orientation, with students who stuttered reporting lower self-esteem and less optimistic life orientation than those who did not stutter. In both groups of students, high victimization scores had statistically significant negative correlations with optimistic life orientation, high self-esteem, and high satisfaction with life scores. Given the increased likelihood of students who stuttered being bullied, the negative relation of adjustment variables and bullying, and the potentially negative long-term effects of bullying, increased vigilance and early intervention are discussed.

Perceptions of self-efficacy in providing multidimensional school-age stuttering therapy among board certified fluency specialists in the United States.

PURPOSE: The purpose of this study was to document fluency specialists' self-efficacy beliefs for providing multidimensional treatment to children who stutter and to identify cognitive, affective, and behavioral correlates of self-efficacy. METHOD: Sixty-six Board Certified Specialists in Fluency in the United States completed an online survey measuring self-efficacy in providing multidimensional stuttering therapy, perceived importance of multidimensional aspects of therapy, feelings of comfort in providing therapy, perceived treatment success, and employment and demographic questions. Open-ended questions were also asked for participants to describe why they chose to specialize and what benefits they received from it. RESULTS: Participants reported high levels of self-efficacy (averages above 9 on a scale from 0 to 10) in speech-related, cognitive, emotional, and social domains of stuttering therapy, as well as high levels of comfort and clinical success. Higher ratings of overall self-efficacy were significantly correlated with beliefs about the importance of multidimensional treatment, τ = 0.27, treatment comfort, τ = 0.25, and self-reported treatment success, τ = .49. Responses indicated that many participants believed that their self-efficacy grew because of specialty certification. CONCLUSION: Although not the same as treatment outcome data, self-efficacy among clinical service providers is an important variable to consider. Board Certified Specialists in Fluency in the United States report very high levels of self-efficacy for school-age stuttering treatment. The process of certification helps to increase self-efficacy and provides a means for advertising competence in stuttering treatment. This information could help in recruiting the next generation of fluency specialists.